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Blockade of oncogenic NOTCH1 with the SERCA inhibitor CAD204520 in T cell acute lymphoblastic leukemia

DOI: 10.1016/j.chembiol.2020.04.002 DOI Help

Authors: Matteo Marchesini (University of Parma) , Andrea Gherli (University of Parma) , Anna Montanaro (University of Parma) , Laura Patrizi (University of Perugia) , Claudia Sorrentino (University of Parma) , Luca Pagliaro (University of Parma) , Chiara Rompietti (University of Perugia) , Samuel Kitara (Harvard Medical School) , Sabine Heit (University of Oxford) , Claus E. Olesen (Aarhus University) , Jesper V. Møller (Aarhus University) , Monia Savi (University of Parma) , Leonardo Bocchi (University of Parma) , Rocchina Vilella (University of Parma) , Federica Rizzi (University of Parma; INBB – Biostructures and Biosystems National Institute) , Marilena Baglione (University of Parma) , Giorgia Rastelli (University of Parma) , Caterina Loiacono (University of Parma) , Roberta La Starza (University of Perugia) , Cristina Mecucci (University of Perugia) , Kimberly Stegmaier (Harvard Medical School) , Franco Aversa (University of Parma) , Donatella Stilli (University of Parma) , Anne-Marie Lund Winther (Cado Biotechnology IvS) , Paolo Sportoletti (University of Perugia) , Maike Bublitz (University of Oxford) , William Dalby-Brown (Cado Biotechnology IvS) , Giovanni Roti (University of Parma)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Chemical Biology

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 18069

Open Access Open Access

Abstract: The identification of SERCA (sarco/endoplasmic reticulum calcium ATPase) as a target for modulating gain-of-function NOTCH1 mutations in Notch-dependent cancers has spurred the development of this compound class for cancer therapeutics. Despite the innate toxicity challenge associated with SERCA inhibition, we identified CAD204520, a small molecule with better drug-like properties and reduced off-target Ca2+ toxicity compared with the SERCA inhibitor thapsigargin. In this work, we describe the properties and complex structure of CAD204520 and show that CAD204520 preferentially targets mutated over wild-type NOTCH1 proteins in T cell acute lymphoblastic leukemia (T-ALL) and mantle cell lymphoma (MCL). Uniquely among SERCA inhibitors, CAD204520 suppresses NOTCH1-mutated leukemic cells in a T-ALL xenografted model without causing cardiac toxicity. This study supports the development of SERCA inhibitors for Notch-dependent cancers and extends their application to cases with isolated mutations in the PEST degradation domain of NOTCH1, such as MCL or chronic lymphocytic leukemia (CLL).

Journal Keywords: NOTCH1; NOTCH1 mutation; PEST mutation; T cell acute lymphoblastic leukemia (T-ALL); mantle cell lymphoma (MCL); SERCA; thapsigargin; CAD204520; P-type ATPases screening; crystal structure

Diamond Keywords: Leukaemia

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 14/05/2020 11:48


Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)